About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.1458C>T, p.(Phe486=)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen PIK3CA VCEP v1.1. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 0
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 v1.1 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: none; combination = no applied criteria, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
19 / 1,613,762 alleles
gnomAD v4.1: 19 / 1,613,762 alleles. Recorded AF 1.17737e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.01937e-06; MAF= 0.00080%, 2/249396 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76766e-05; MAF= 0.00177%, 2/113144 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions
3 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1, with the data and sources behind each one.
29 criteria with recorded statuses: 0 met · 12 not met · 2 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006218.4:c.1458C>T is a synonymous variant (p.Phe486=) in PIK3CA exon 9. Under the ClinGen Brain Malformations VCEP v1.1, PVS1, PP1, PP3, PP4, PP5, PM6, BS4, BP1, and BP6 are not applicable.
PS1, PS5, and PM5 are not applicable because the variant is synonymous and produces no amino acid change.
The variant is present in gnomAD v2.1 (2/249,396 alleles; 0.0008%) and v4.1 (19/1,613,762 alleles; 0.00118%), exceeding the VCEP PM2_Supporting threshold of ≤1 allele. The allele frequency does not reach BA1 (>0.0926%) or BS1 (>0.0185%) thresholds. Zero homozygotes are observed (BS2 not met).
Residue 486 lies outside both PIK3CA critical functional domains defined by the VCEP Table 4 (AA 322-483 and AA 797-1068); PM1_Supporting is not met.
No functional studies, de novo occurrences, brain malformation case reports, or co-segregation data were identified for this variant. ClinVar classifies it as Likely benign (3 clinical laboratories, single submitter, no expert panel review).
BP4 and BP7 remain unassessed due to missing splicing prediction (varSEAK, MaxEntScan) and conservation (PhyloP) data. SpliceAI predicts no splice impact (max delta 0.01).
No reviewable publications contained variant-specific evidence. All ClinVar-associated PMIDs are guideline or policy documents that do not mention NM_006218.4:c.1458C>T.
No criteria match.
Not met · 12 · evaluated, threshold not reached
PS2 No de novo occurrence has been reported for this variant. VCEP PS2 requires confirmed de novo status with or without tissue mosaicism evidence; no such data are available in the case record. Details ▾Hide ▴
Evidence considered
- No de novo data for this variant in ClinVar submissions
- literature
- or case materials.
Still missing
- No parental or tissue mosaicism studies available.
Sources
PS3 No well-established in vitro or in vivo functional studies are available for this variant. OncoKB classifies the variant as Unknown Oncogenic Effect with no curated PMIDs. No functional data were identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no curated functional literature. No functional data found in publications.
Still missing
- No functional studies available for this variant.
Sources
PS4 VCEP PS4 requires PM2 first. PM2 is not met (variant exceeds the ≤1 allele threshold in gnomAD). Additionally, no brain malformation phenotype cases have been reported in the literature for this variant. The variant is classified as Likely benign in ClinVar by three clinical laboratories. Details ▾Hide ▴
Evidence considered
- PM2 not met (2 alleles gnomAD v2.1
- 19 alleles v4.1
- VCEP threshold ≤1). ClinVar: Likely benign (3 clinical labs). No brain malformation cases identified in literature.
Still missing
- No brain malformation cases reported.
Sources
PM1 VCEP PM1_Supporting requires location within a Table 4 critical functional domain. PIK3CA domains are kinase domain AA 322-483 and AA 797-1068. Residue 486 lies outside both approved domains (3 residues beyond the N-terminal kinase lobe boundary at 483). Details ▾Hide ▴
Evidence considered
- Position 486 is not within PIK3CA Table 4 domains (AA 322-483
- 797-1068). Not a cancerhotspots.org significant residue.
Sources
PM2 VCEP PM2_Supporting requires ≤1 allele in ethnically matched control populations. This variant is present in gnomAD v2.1 with 2 alleles (AF 0.0008%) and gnomAD v4.1 with 19 alleles (AF 0.00118%), exceeding the VCEP threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 2/249
- 396 alleles (0.0008%). gnomAD v4.1: 19/1
- 613
- 762 alleles (0.00118%). VCEP PM2 threshold: ≤1 allele.
Sources
PP2 VCEP PP2 requires a missense constraint z-score > 3.09 in gnomAD. This variant is synonymous, not missense. Additionally, no missense z-score data was retrieved for this case. Details ▾Hide ▴
Evidence considered
- Variant is synonymous
- PP2 missense constraint metric does not apply. No z-score data available.
Still missing
- Missense constraint z-score not retrieved.
Sources
BA1 VCEP BA1 threshold is allele frequency > 0.0926%. The highest observed population frequency is 0.00177% (gnomAD v2.1 European non-Finnish) and 0.00160% (gnomAD v4.1 remaining individuals), both well below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- Max population AF gnomAD v2.1: 0.00177% (NFE). gnomAD v4.1: 0.00160% (remaining). VCEP BA1 threshold: >0.0926%.
Sources
BS1 VCEP BS1 threshold is allele frequency > 0.0185%. The highest observed population frequency is 0.00177% (gnomAD v2.1), below the BS1 threshold. Details ▾Hide ▴
Evidence considered
- Max population AF: 0.00177%. VCEP BS1 threshold: >0.0185%. Below threshold.
Sources
BS2 VCEP BS2 requires ≥3 homozygotes in gnomAD or ≥3 well-phenotyped heterozygous family members. Zero homozygotes are observed; no family data are available. Details ▾Hide ▴
Evidence considered
- Zero homozygotes in gnomAD v2.1 and v4.1. No family phenotype data available.
Still missing
- No family segregation or phenotype data.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate a benign effect for this variant. No functional data were identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
- No functional studies demonstrating no damaging effect. OncoKB: Unknown Oncogenic Effect
- no curated PMIDs.
Still missing
- No functional studies available.
Sources
BP2 No evidence of this variant observed in cis or trans with a known pathogenic variant in PIK3CA. Details ▾Hide ▴
Evidence considered
- No reports of cis/trans occurrence with a pathogenic PIK3CA variant.
Still missing
- No phase data available.
Sources
BP5 No alternate molecular basis for disease has been identified that would explain the phenotype independently of this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause identified in the case materials.
Still missing
- Case-specific phenotype and alternate diagnosis information not provided.
Sources
Not assessed · 2 · no assessment recorded
BP4 VCEP BP4 is applicable to synonymous variants but requires 2 of 3 splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact. Only SpliceAI data is available (max delta score = 0.01, no impact predicted). varSEAK and MaxEntScan data are not available; the 2-of-3 requirement cannot be satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no impact). varSEAK: not available. MaxEntScan: not available. 1 of 3 tools available.
Still missing
- varSEAK and MaxEntScan splicing prediction scores needed to complete BP4 assessment.
Sources
BP7 VCEP BP7 is applicable to synonymous variants and requires non-conservation (PhyloP score < 0.1 or absence across vertebrates). SpliceAI predicts no splice impact (max delta 0.01), satisfying the splicing component. However, PhyloP conservation data was not retrieved for this variant; the nucleotide conservation requirement cannot be evaluated. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no splice impact). PhyloP score: not available. Conservation assessment incomplete.
Still missing
- PhyloP conservation score needed to complete BP7 assessment.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPVCEP declares PVS1 not applicable for PIK3CA; the disease mechanism is gain of function, and loss of function has not been established as a disease mechanism for brain malformations. Details ▾Hide ▴
Evidence considered
- VCEP Brain Malformations specification v1.1 declares PVS1 N/A for PIK3CA (gain-of-function mechanism).
Sources
PS1 N/AThis variant is synonymous (p.Phe486=) and does not result in an amino acid change; PS1 requires the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Evidence considered
- Variant produces no amino acid change
- PS1 is not applicable to synonymous variants.
Sources
PM3 VCEPBrain malformations are not recessive disorders; VCEP declares PM3 not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPVariant is a single-nucleotide substitution, not an in-frame deletion/insertion or stop-loss. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to missense changes at an amino acid residue where a different pathogenic missense change has been seen. This variant is synonymous (p.Phe486=) with no amino acid change; PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant class is synonymous
- not missense. PM5 candidate search confirmed not applicable.
Sources
cspec ↗pm5_candidates
PM6 VCEPVCEP declares PM6 not applicable; PM6 is addressed by PS2 in this framework. Details ▾Hide ▴
Evidence considered
- VCEP Brain Malformations specification v1.1: PM6 is 'Addressed by PS2 — N/A.'
Sources
PP1 VCEPVCEP declares PP1 not applicable because disease-causing variants in brain malformation disorders are germline mosaic, de novo, or mosaic, making co-segregation analysis infeasible. Details ▾Hide ▴
Evidence considered
- VCEP: 'Not applicable since disease-causing variants are germline mosaic
- de novo or mosaic.'
Sources
PP3 VCEPVCEP declares PP3 not applicable. Details ▾Hide ▴
PP4 VCEPVCEP declares PP4 not applicable; phenotype specificity is accounted for under PS4 in this framework. Details ▾Hide ▴
PP5 VCEPVCEP declares PP5 not applicable. Details ▾Hide ▴
BS4 VCEPVCEP declares BS4 not applicable because disease-causing variants are de novo, germline mosaic, or post-zygotic. Details ▾Hide ▴
Evidence considered
- VCEP: 'Not applicable as these are de novo
- germline mosaic or post-zygotic mutations.'
Sources
BP1 VCEPVCEP declares BP1 not applicable for PIK3CA; the disease mechanism is gain of function, not loss of function. Details ▾Hide ▴
Evidence considered
- VCEP Brain Malformations specification v1.1: BP1 is N/A (disease mechanism is GOF).
Sources
BP3 VCEPVariant is a substitution, not an in-frame deletion/insertion. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPVCEP declares BP6 not applicable. Details ▾Hide ▴
PS5 N/AThis variant is synonymous (p.Phe486=) and does not result in an amino acid change. PS5 is not defined in the Brain Malformations VCEP and would require a missense change at a residue with known pathogenic variation. Details ▾Hide ▴
Evidence considered
- Variant is synonymous
- no amino acid change to compare against other pathogenic variants at this residue.
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.1458C>T
- Protein (HGVS p.)
- NP_006209.2:p.(Phe486=)
- GRCh38
- chr3:179210484 C>T
- GRCh37
- chr3:178928272 C>T
- ClinVar
- 696899
Gene diagram
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.4. Select a row to find it on the plot.
PIK3CANM_006218.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PIK3CA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
19 / 1,613,762 alleles
AF 1.18e-05 · 0 homozygotes · FAF 9.53e-06
gnomAD v2.1
2 / 249,396 alleles
AF 8.02e-06 · 0 homozygotes · FAF 2.94e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-05 · 19 / 1,613,762 alleles · 0 hom · FAF 9.5e-06
| Remaining individuals1 / 62,476 | 1.6e-05 |
| European (non-Finnish)18 / 1,179,882 | 1.5e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 8e-06 · 2 / 249,396 alleles · 0 hom · FAF 2.9e-06
| European (non-Finnish)2 / 113,144 | 1.8e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.17737e-05; MAF= 0.00118%, 19/1613762 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60061e-05; MAF= 0.00160%, 1/62476 alleles, homozygotes = 0); grpmax FAF= 9.53e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.01937e-06; MAF= 0.00080%, 2/249396 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76766e-05; MAF= 0.00177%, 2/113144 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 VCEP BP4 is applicable to synonymous variants but requires 2 of 3 splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact. Only SpliceAI data is available (max delta score = 0.01, no impact predicted). varSEAK and MaxEntScan data are not available; the 2-of-3 requirement cannot be satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no impact). varSEAK: not available. MaxEntScan: not available. 1 of 3 tools available.
Still missing
- varSEAK and MaxEntScan splicing prediction scores needed to complete BP4 assessment.
Sources
BP7 VCEP BP7 is applicable to synonymous variants and requires non-conservation (PhyloP score < 0.1 or absence across vertebrates). SpliceAI predicts no splice impact (max delta 0.01), satisfying the splicing component. However, PhyloP conservation data was not retrieved for this variant; the nucleotide conservation requirement cannot be evaluated. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no splice impact). PhyloP score: not available. Conservation assessment incomplete.
Still missing
- PhyloP conservation score needed to complete BP7 assessment.
Sources
PP3 VCEPVCEP declares PP3 not applicable. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 23652378 ↗A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.Expert opinion document on EU neonatal screening policies and rare disease public health actions. NM_006218.4:c.1458C>T was not identified in this paper.Does not name this variant
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PMID 25730230 ↗Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.Joint statement on expanded carrier screening in reproductive medicine from ACMG, ACOG, NSGC, and SMFM. NM_006218.4:c.1458C>T was not identified in this paper.Does not name this variant
-
PMID 23519317 ↗Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.Schaefer GB et al. · 2013ACMG practice guideline on clinical genetics evaluation for identifying the etiology of autism spectrum disorders (2013 revision). NM_006218.4:c.1458C>T was not identified in this paper.Does not name this variant
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PMID 23037933 ↗Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.Therrell BL et al. · 2013Recommendations on newborn screening bloodspot collection device serial numbers from the HHS Advisory Committee on Heritable Disorders. NM_006218.4:c.1458C>T was not identified.Does not name this variant
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PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.Guidelines for parental permission in pilot newborn screening research from the NBSTRN. NM_006218.4:c.1458C>T was not identified.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc comprehensive refinement of ACMG-AMP variant classification criteria. NM_006218.4:c.1458C>T was not identified.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
19 / 1,613,762 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
3 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/467907148
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/696899/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178928272-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179210484-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-179210484-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.1458…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/F486=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.1458C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.17737e-05; MAF= 0.00118%, 19/1613762 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60061e-05; MAF= 0.00160%, 1/62476 alleles, homozygotes = 0); grpmax FAF= 9.53e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.01937e-06; MAF= 0.00080%, 2/249396 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76766e-05; MAF= 0.00177%, 2/113144 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories). (ClinVarID = 696899)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.